Sepsis remains the leading cause of mortality in our intensive care units, and is the most common cause of late organ injury after trauma and surgical intervention. Despite improved supportive care, mortality from severe sepsis and organ failure has only modestly improved. During the initial funding period of this award, we observed that a novel population of immature myeloid cells, phenotypically similar to the myeloid derived suppressor cells (MDSCs) described in advanced cancer, expand dramatically in severe sepsis, in response to burns and infection, and after exposure to specific TLR ligands. Initially, we presumed that these cells played a comparable role in sepsis to the role they play in advanced cancer: to suppress adaptive immunity. In fact, data have accumulated that this expansion of MDSCs may in fact, not be summarily detrimental to the septic host, but rather part of the beneficial response to severe sepsis aimed at supporting innate immunity. Our overarching hypothesis is that expansion of MDSCs plays an essential role in sepsis by sustaining innate immunity and immune surveillance in the face of adaptive immune suppression and reduced APC function. The three specific aims are to: (1) To determine the cellular mechanisms by which MDSCs induce an anti-microbial response in acute bacterial infections, including the production of reactive oxygen and nitrogen species. (2) To determine whether the expansion of MDSCs in polymicrobial sepsis is required for the maintenance of innate immune function, and can compensate for the adaptive immune suppression that leads to increased susceptibility and/or mortality to secondary infections, and (3) To examine whether a similar expansion of MDSC populations occurs in human sepsis or severe trauma, as documented by their appearance in the circulation, and in organs/tissues of the lymphoid and reticuloendothelial systems. This program will lead to a better understanding of the MDSC expansion that occurs in sepsis and trauma. Further, this work will elucidate whether MDSCs play a beneficial or pathologic role (or both) in severe sepsis, and whether therapeutic efforts should be targeted at either suppressing or expanding their role(s). Finally, these studies will lead to a final resolutin whether MDSC expansion also occurs in human sepsis and trauma and is associated with the severity of the inflammation. PUBLIC HEALTH RELEVANCE: Recent findings suggest that murine models of severe sepsis are associated with the expansion of a heterogenous group of myeloid derived suppressor cells. Studies proposed here will determine whether the expansion of these populations is beneficial or detrimental to outcome from sepsis, whether they act through the production of reactive oxygen or nitrogen species, and whether a similar expansion is seen in human sepsis and trauma.